Worldwide nearly 400,000 cases of oral cancer are diagnosed annually. Most are treated with radiotherapy, which saves the life of the patient but results in radiation-induced complications such as xerostomia, severe dentition breakdown and loss of masticatory function. The present understanding of post-radiation dentition breakdown, with radiation-induced xerostomia considered the most significant etiological factor, does not adequately explain the observed post-radiation lesion characteristics with initial enamel loss at loading and flexure sites (cervical/incisal/cuspal). Our recent clinical study data indicate for the first time a direct and independent link between tooth-level radiation dose and the severity of the individual tooth lesion. Thus, future improvements for preventing and treating post-radiation dentition breakdown depend on new knowledge of the underlying mechanism of radiation-induced tooth damage. A mechanism explaining radiation-induced breakdown at the tooth level is currently unknown. A potential explanation could be linked to reports of in vitro radiation-induced changes in the physical properties of enamel and dentin. However, dentition breakdown following radiotherapy tends to start within the first year and become more severe with time. We propose that radiation may cause a direct change in tooth structure, but other factors must also be considered in order to explain the elapsed time between radiotherapy and dentition breakdown. One important contributing factor could be cyclic occlusal loading. We expect that effects of radiotherapy on the structure of teeth become more evident with masticatory function over time. Another mechanistic factor could be radiation-induced activation of matrix metalloproteinases (MMPs) in the dentinal tubules as well as the collagen matrix. MMP activation followed by collagen degradation could contribute to property and structure changes and also partially explain the elapsed time. Our central hypothesis is that radiotherapy could cause direct changes in collagen and mineral structures and possible indirect changes through increased activity of tooth-associated MMPs leading to additional collagen matrix degradation. Cumulatively, these effects could result in property/structure changes of dentin, enamel and the DEJ that would adversely affect the stress distribution pattern under functional loading. The specific aims will determine whether 1) radiotherapy changes the mechanical properties of dentin, enamel and the DEJ; 2) resultant mechanical property differences correlate with chemical composition/structure changes; 3) occlusal/functional loading further alters mechanical properties and structure of radiated teeth; 4) radiation-induced property/structure changes negatively affect load transfer at the DEJ as predicted by finite element modeling; 5) radiotherapy increases activity of tooth-associated enzymes like MMPs leading to additional collagen degradation. The proposed study outcomes should identify mechanism(s) responsible for radiotherapy effects on the dentition and the altered structure/function characteristics of radiated teeth leading to improved preventive and restorative treatments for oral cancer patients post-radiation.